The objective of this research project is the elucidation of epigenetic control mechanisms of leukemia. As a model, we will use murine leukemia virus (MuLV) as the leukemogenic agent and mouse lymphocytes as the target cells. The interactions between MuLV and lymphocytes is regulated by several mechanisms at the target cell level. To be able to study this we developed a novel method of infection of isolated, purified lymphocytes with MuLV in semipermeable chambers implanted in vivo. Using this method, as well as a method in infection in vitro, it was shown that a given MuLV replicates in one class of lymphocytes, i.e., B cells, but not in the other class, i.e., T cells. Furthermore, there appear to be permissive and resistant sub-populations within each class. The nature of the resistance and permissiveness to MuLV related to lymphocyte differentiation will be studied. Another regulatory mechanism is related to the fact that effective infection of permissive lymphocytes requires activation of the target cell either with mitogen or with a specific antigen. The molecular basis of this will be studied. Differentiation and activation of lymphocytes is regulated by various hormonelike lymphokines which, in turn, regulate the leukemogenesis. We showed examples of this control already, and will study it further. Infection with MuLV also results in suppression of the target lymphocytes' functions. However, it appears that this is not directly related to virus replication and that even non-permissive lymphocytes might be suppressed. In this respect, the immunosuppression is regarded as an independent function of the virus and as such will be studied using various temperature-sensitive mutants of MuLV. Finally, functional properties of a given class of lymphocytes are under control of another population of regulator cells. This interaction is characteristic of the lymphoid system and may represent another control mechanism of leukemogenesis.